ORGANIC LETTERS
Stereospecific Route to 5,11-Methanomorphanthridine Alkaloids via Intramolecular 1,3-Dipolar Cycloaddition of Nonstabilized Azomethine Ylide: Formal Total Synthesis of (±)-Pancracine
2005 Vol. 7, No. 17 3713-3716
Ganesh Pandey,*,† Prabal Banerjee,† Ravindra Kumar,† and Vedavati G. Puranik‡ DiVision of Organic Chemistry (Synthesis) and Center for Material Characterization, National Chemical Laboratory, Pune 411008, India
[email protected] Received June 7, 2005
ABSTRACT
The core structure of the complex pentacyclic 5,11-methanomorphanthridine alkaloids is constructed stereospecifically in one step employing an intramolecular [3 + 2]-cycloaddition of nonstabilized azomethine ylide as the key step. The strategy is demonstrated by accomplishing the formal total synthesis of (±)-pancracine.
The 5,11-methanomorphanthridine alkaloids, belonging to the subclass Amaryllidaceae, were first isolated by Wildman and co-workers in 1955.1 These natural products, produced by various plant species such as Pancratium, Narcissus, and BrunsVigia, have a unique pentacyclic framework. In general, alkaloids of this group, (-)-pancracine (1), (-)-montanine (2), (-)-coccinine (3), and (-)-brunsvigine (4), possess identical structural features except for the oxygen substitutions in the E-ring (methoxy vs hydroxyl)2 and stereochemistry at C-2 and C-3. Due to unique structural features and important biological activities3 associated with these alka-
loids, considerable attention is directed from synthetic chemists toward the total syntheses of these alkaloids.
†
Division of Organic Chemistry (Synthesis). Center for Material Characterization. (1) (a) Wildman, W. C.; Kaufman, C. J. J. Am. Chem. Soc. 1955, 77, 1249. (b) Dry, L. J.; Poynton, M. E.; Thompson, M. E.; Warren, F. L. J. Chem. Soc. 1958, 4701. (c) Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.; Wildman, W. C. J. Org. Chem. 1960, 25, 2153. (d) Wildman, W. C.; Brown, C. L. J. Am. Chem. Soc. 1968, 90, 6439. (2) (a) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, pp 323. (b) Lewis, J. R. Nat. Prop. Rep. 1993, 10, 291. (c) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.; Mathee, S. Phytochemistry 1995, 40, 307. ‡
10.1021/ol051321o CCC: $30.25 Published on Web 07/21/2005
© 2005 American Chemical Society
Literature scrutiny revealed that methodologies pertaining to the construction of the core pentacyclic 5,11-methanomorphanthridine skeleton (5) have mainly been limited to either Pictet-Spengler reaction from 6, intramolecular alkylation of 7, or intramolecular radical cyclization from 8. (3) Southon, I. W.; Buckinghham, J. Dictionary of the Alkaloids; Chapman & Hall; New York, 1989; pp 229, 735.
Figure 1. Summary of the reported strategies for assembling the 5,11-methanomorphanthridine class of alkaloids.
(Figure 1) However, in all these strategies, synthesis is elaborated from a precursor having the proper stereochemistry at C-4a and C-11a and a relative disposition of the C-12 methylene group of 5 that involved their construction in a stepwise manner. Hoshino and co-workers4 have accomplished the synthesis of 1-4 in racemic form from a precursor of type 7, obtained from the Pictet-Spengler reaction of a corresponding cyclohexane derivative. Weinreb and Jin5 also utilized similar cyclization strategy from a compound of type 7 in their synthesis of (-)-pancracine (1) and (-)-coccinine (4). In another approach, Hoshino and coworkers6 have used radical cyclization from a precursor of type 8 to construct skeleton 5. Overman,7 Pearson,8 Ikeda,9 Sha,10 and Banwell11 have used a precursor of type 6 in their respective elaborations of these alkaloids. We viewed the synthesis of these alkaloids differently, as depicted retrosynthetically in Scheme 1, employing an
Scheme 1.
Retrosynthetic Analysis
intramolecular 1,3-dipolar cycloaddition strategy of a nonstabilized azomethine ylide (AMY) for the construction of 3714
Figure 2. Empirical view of transition state 11 (hydrogens have been omitted for simplicity).
the core 5,11-methanomorphanthridine CD-ring system in one step. It may be mentioned that this concept originated from our ongoing research activities in the area of alkaloid syntheses12 involving a nonstabilized azomethine ylide cycloaddition strategy, generated by sequential double desilylation of R,R′-bis(trimethylsilylmethyl)alkylamines13 as the key step. In this communication, we explore a conceptually new route for the expedient construction of 9 toward the total synthesis of (()-pancracine (1). An analysis of the steric repulsion present in A and B indicated that endo attack (A) would be preferred over the more encumbered exo alternative (B) (Figure 2). Such cycloaddition was also envisaged to provide core 5,11methanomorphanthridine skeleton 10 with the stereochemical dispositions required for assembling a suitably equipped E-ring for further elaboration by intramolecular cycloalkylation reaction. (4) (a) Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991, 32, 7079. (b) Ishizaki, M.; Hoshino, O. J. Org. Chem. 1992, 57, 7285. (5) (a) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050. (b) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5773. (6) Ishizaki, M.; Kurihara, K.-I.; Tanazawa, E.; Hoshino, O. J. Chem. Soc., Perkin Trans. 1 1993, 101. (7) (a) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005. (b) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662. (8) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724. (9) Ikeda, M.; Hamada, M.; Yamashita, T.; Ikegami, F.; Sato, T.; Ishibashi, H. Synlett 1998, 1246. (10) (a) Sha, C.-K.; Huang, C.-M.; Hong, A.-W.; T.-H. Pure Appl. Chem. 2000, 72, 1773. (b) Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
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Our synthetic journey began with the preparation of principal precursor 12 in 70% yield by following the simple steps as shown in Scheme 2.
Scheme 2.
Synthesis of 12
Refluxing a mixture of 14 (1 equiv) and 15 (1.25 equiv) in CH3CN in the presence of anhydrous K2CO3 gave the corresponding coupled alcohol, which upon benzoylation gave 13 in 81% yield. Our initial attempt of Heck coupling14 between 13 and methyl vinyl ketone (MVK) by following usual reported procedures such as PdCl2(CH3CN)2 in THF15a or Pd(OAc)2/n-Bu4NCl in DMF at room temperature,15b however, failed to provide 12 in satisfactory yield. Finally, with little experimentation and optimization, we succeeded in obtaining 12 in 60% yield using Pd(OAc)2 as the catalyst and with an increased amount of MVK (8 equiv). One of the coupling components (14) used in this reaction was prepared very easily from the commercially available piperonyl alcohol in 70% yield in two steps using known procedures.5b,16 The synthesis of another component (15) is shown in Scheme 3.
Scheme 3.
Scheme 4.
Cycloaddition of 11
Synthesis of 15
The N-Boc cyclic amine 16, synthesized easily in two steps from commercially available 3-amino propanol, upon meta(11) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Kemmler, M. J. Chem. Soc., Perkin Trans. 1 2001, 1345. (12) (a) Pandey, G.; Laha, J. K.; Lakshmaiah, G. Tetrahedron 2002, 58, 3525. (b) Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000, 2, 2299. (c) Pandey, G.; Laha, J. K.; Mohankrishnan, A. K. Tetrahedron Lett. 1999, 40, 6065. (d) Pandey, G.; Sahoo, A. K.; Gadre, S. R.; Bagul, T. D.; Phalgune, U. D. J. Org. Chem. 1999, 64, 4990. (e) Pandey, G.; Bagul, T. D.; Sahoo, A. K. J. Org. Chem. 1998, 63, 760. (f) Pandey, G.; Lakshmaiah, G.; Ghatak, A. Tetrahedron Lett. 1993, 34, 7301. (13) (a) Pandey, G.; Lakshmaiah, G.; Kumaraswamy, G. J. Chem. Soc., Chem. Commun. 1992, 1313. (b) Pandey, G.; Lakshmaiah, G. Tetrahedron Lett. 1993, 34, 4861. (14) For recent reviews of Heck reaction, see: (a) Bra¨se, S.; de Meijere, A. In Metal-Catalysed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: New York, 1998; Chapter 3. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
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lation using s-BuLi/TMEDA in THF at -78 °C and quenching with TMSCl, gave 17 in 92% yield.17 Deprotection of both N,O-acetal as well as N-Boc moieties using 1 N HCl in refluxing dioxane produced corresponding free amine 18 in 87% yield, which upon alkylation with (iodomethyl)trimethylsilane in the presence of anhydrous K2CO3 in CH3CN gave 15 in 80% yield. The crucial intramolecular cycloaddition reaction of the azomethine ylide generated from 12, to our delight, gave 10 as a single diastereoisomer in 56% yield. The cycloaddition reaction was performed by slow addition of 12 (1 equiv) to a stirring heterogeneous mixture of the flame-dried Ag(I)F (2.5 equiv) in dry CH3CN. The cycloadduct 10 was fully characterized by 1H NMR, 13C NMR, and mass spectral data. The stereochemical assignments, as shown in Scheme 4, are
based on extensive COSY and NOESY NMR spectral studies. To proceed further from 10, we subjected it to the usual debenzoylation reaction (LiOH/MeOH, rt), which, however, provided unexpected epimerized alcohol 20 in 98% yield (confirmed by X-ray crystallography).18 Although unepimerized alcohol 19 could be obtained from 10 by stirring with LiOH/MeOH at 0 °C (Scheme 4), we decided to continue further with 20 itself, as the C11a stereochemistry at this stage was irrelevant for final natural product synthesis. Intramolecular cycloalkylation19 of the corresponding me(15) (a) Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035 (b) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667. (16) (a) Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am. Chem. Soc. 1990, 112, 6959. (b) Wilson, C. V.; Janseen, D. E. Organic Synthesis; Wiley: New York, 1963; Collect. Vol. IV, pp 547. (17) Beak, P.; Yum, E. K. J. Org Chem. 1993, 58, 823. 3715
sylate derivative of 20 using LDA/THF at -78 °C very surprisingly produced 24 in 65% yield, indicating the involvement of a thermodynamic enolate 22 in this rearrangement (Scheme 5). Successful transformation of 20 to 23 (epi-9) was finally achieved in 58% yield involving kinetic enolate20 21, generated from 20 in the presence of KHMDS/ THF at -78 °C. Involvement of an azetidinium salt-type intermediate from 20 in the formation of 23 and 24, neither can be supported nor ruled out at this stage. To demonstrate the significance of our strategy, we decided to complete the formal total synthesis of (()pancracine 1. The pivotal ∆1,11a double bond from 23 leading to the formation of 25 (71% yield) was created by the reductive elimination of the corresponding enol triflate using Pd(PPh3)4/Et3SiH in THF.21 The required enol triflate from 23 was generated by the reaction of the corresponding lithium enolate of 23 with the Comins reagent.22 All spectral data of 25 matched very well with the values reported by Overman et al.,7 who have also elaborated 25 in a couple of steps to (()-pancracine 1. In conclusion, we have developed a short and conceptually new route for the stereospecific construction of the core structure of 5,11-methanomorphanthridine alkaloids in one step. The success of this strategy is demonstrated by accomplishing the formal total synthesis of (()-pancracine (18) X-ray analysis of 20: C16H19NO4, Mr ) 289.32, crystal dimensions 0.40 × 0.38 × 0.13, Bruker SMART APEX CCD diffractometer, Mo KR radiation, multiscan data acquisition, a ) 5.7666(5), b ) 9.7162(8), c ) 13.4268(11) Å, R ) 98.029(1), β ) 100.091(1), γ ) 97.602(1)°, V ) 723.8(1) Å3, Z ) 2, Dc ) 1.327 mg m-3, triclinic, space group P-1, µ (Mo KR) ) 0.095 mm-1, of 7005 reflections measured, 2539 unique [I > 2σ(I)], R value 0.0441, wR2 ) 0.1167. All data were corrected for Lorentzian, polarization, and absorption effects. SHELX-97 was used for structure solution and full matrix least squares refinement on F2. Hydrogen atoms were included in the refinement as per the riding model. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-271169. (19) (a) Petrovic, G.; Cekovic, Z. Org. Lett. 2000, 2, 3769. (b) House, H. O.; Phillips, W. V.; Sayer, T. S. B.; Yau, C. C. J. Org. Chem. 1978, 43, 700. (20) Howard, M. H.; Sardina, F. J.; Rapoport, H. J. Org. Chem. 1990, 55, 2829. (21) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033. (22) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
3716
Scheme 5.
Formal Total Synthesis of (()-Pancracine 1
1. The asymmetric version of this approach, along with an alternative strategy for constructing the E-ring and synthesis of some other important alkaloids of this class, is in progress and will be revealed in a full paper shortly. Acknowledgment. We are thankful to the Department of Science and Technology, New Delhi, for financial support. P.B. and R.K. thank CSIR, New Delhi, for the award of Research Fellowships. Supporting Information Available: Experimental procedures and characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OL051321O
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